Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) is under the control of a closely associated SR protein named phospholamban (PLN). Dephosphorylated PLN inhibits the SR Ca(2+) pump, whereas phosphorylation of PLN, at either Ser(16) by PKA or Thr(17) by calmodulin-dependent protein kinase II (CaMKII), reverses this inhibition, thus increasing SERCA2a activity and the rate of Ca(2+) uptake by the SR. This would in turn lead to an increase in the velocity of relaxation, SR Ca(2+) load, and myocardial contractility. Thus, PLN is a major determinant of cardiac contractility and relaxation. Although in the intact heart, beta-adrenoceptor stimulation results in phosphorylation of PLN at both Ser(16) and Thr(17) residues, the role of Thr(17) site has long remained equivocal. In this review, we attempt to highlight the signaling cascade and the physiological relevance of the phosphorylation of this residue in the heart under both physiological and pathological situations.
Cardiovasc Res 2005 Dec 01
PMID:Role of phospholamban phosphorylation on Thr17 in cardiac physiological and pathological conditions. 1622 37

Calcium channel blockers (CCBs) are widely used in clinical practice, and have been reported to be effective in preventing the progression of atherosclerosis. We examined whether various types of calcium channel blockers affected the expression of ATP binding cassette transporter A1 (ABCA1), a factor contributing to anti-atherogenesis. Undifferentiated monocytic cell line, THP-1 cells were maintained in RPMI 1640 medium and treated with different kinds of calcium channel blockers. Among the calcium channel blockers tested, aranidipine and efonidipine increased ABCA1 protein expression without an increase in ABCA1 mRNA expression, whereas other calcium channel blockers (eg, nifedipine, amlodipine, and nicardipine) or T-type calcium channel blockers (eg, mibefradil and nickel chloride) failed to upregulate ABCA1 expression. H89, a protein kinase A inhibitor inhibited the aranidipine-induced ABCA1 protein expression, whereas genistein (a tyrosine kinase inhibitor), or AG490 (a JAK-2 inhibitor) had no effects. Neither of these inhibitors suppressed the efonidipine-induced ABCA1 protein expression. Intracellular cAMP levels were elevated only by aranidipine, but not by efonidipine. In conclusion, aranidipine and efonidipine have the ability to induce ABCA1 protein by distinct mechanisms; protein kinase A is involved in the aranidipine-induced ABCA1 upregulation. This non-class effect of calcium channel blockers may potentially offer beneficial action in the treatment of hypertensive subjects with atherosclerosis.
J Cardiovasc Pharmacol 2005 Dec
PMID:Divergent action of calcium channel blockers on ATP-binding cassette protein expression. 1630 3

Ischemic preconditioning is a powerful infarct-sparing intervention. Intensive investigations have revealed many of the signaling steps used to elicit this protection. One of the steps involves activation of nitric oxide synthase (NOS) by phosphorylation, with the production of NO and subsequent activation of guanylyl cyclase, production of cGMP, activation of protein kinase G, opening of mitochondrial KATP channels, and generation of reactive oxygen species. The latter act as second messengers to activate critical kinase cascades that trigger entrance into the preconditioned state. Thus, NO exposure before ischemia can act as a powerful preconditioning mimetic. Elevating NO just prior to or at reperfusion can still be an effective cardioprotective strategy. Activation of NOS or production of NO can be done pharmacologically with exogenous agents to trigger this cascade. Many of these strategies are already available and safe.
Cardiovasc Res 2006 May 01
PMID:Nitric oxide is a preconditioning mimetic and cardioprotectant and is the basis of many available infarct-sparing strategies. 1637 69

Despite nearly twenty years of research into the field of ischemic preconditioning, the actual mechanism of protection remains unclear. However, much progress has been made in elucidating the signal transduction pathways that convey the extracellular signal initiated by the preconditioning stimulus to the intracellular targets of cardioprotection, with many of these pathways involving the activation of a diverse array of survival protein kinase cascades. The powerful protective benefits of ischemic preconditioning have not yet been realised in the clinical arena, not least because of the prerequisite for any preconditioning intervention to be applied prior to the onset of index ischemia, which in the case of an acute myocardial infarction is difficult to institute. In this regard, the newly described phenomenon of ischemic postconditioning, which comprises a cardioprotective intervention that can be applied at the time of myocardial reperfusion, offers a far more attractive and amenable approach to myocardial protection. Interestingly, certain survival protein kinase cascades recruited at the time of myocardial reperfusion appear to be shared by both ischemic preconditioning and postconditioning, thereby offering a potentially common target of cardioprotection. The often disputed roles these different protein kinases play in mediating the cardioprotective effects of ischemic preconditioning and postconditioning are reviewed in this article, and include protein kinases C, G, and A, members of the MAPK family (Erk1/2, p38, JNK and BMK1), the PI3K-Akt cascade, and the JAK-STAT pathway.
Cardiovasc Res 2006 May 01
PMID:Survival kinases in ischemic preconditioning and postconditioning. 1654 52

Several landmark clinical trials suggest that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have additional cardiovascular protective activity that may function independently of their ability to lower serum cholesterol. The cardiovascular protective effects of statins are partly caused by the activation of postnatal neovascularization. At therapeutic doses, statins promote proliferation, migration and survival of endothelial cells, induce mobilization and differentiation of bone marrow-derived endothelial progenitor cells by stimulating the serine/threonine protein kinase Akt (also known as protein kinase B) and nitric oxide (NO) signal pathway. However, at excessive doses, statins may decrease protein isoprenylation as well as inhibit endothelial cell growth and migration. NO is an important signaling molecule that regulates a wide range of physiological and pathological processes in different tissues. There is substantial evidence that effective neovascularization requires endothelium-derived NO. Statins have pleiotropic effects on the expression and activity of endothelial nitric oxide synthase (eNOS) and lead to improved NO bioavailability. NO plays an important role in the effects of statins on neovascularization. In this review, we focus on the effects of statins on neovascularization and highlight specific novel targets, such as endothelial progenitor cells and NO.
Cardiovasc Drug Rev 2005
PMID:Statins, nitric oxide and neovascularization. 1661 29

Our understanding of the end-effectors involved in preconditioning protection is still very limited. This is partially due to an incomplete knowledge of the mechanisms responsible for acute sarcolemmal rupture and cell death during the first minutes of reperfusion, including the relative roles of hypercontracture-mediated sarcolemmal rupture and mitochondrial permeability transition pore (MPTP) opening-mediated cell death. In the present article, the role of proposed end-effectors of preconditioning protection, defined as molecules directly involved in cell death that are modified by ischemic preconditioning (IP), is examined. IP attenuates hypercontracture-mediated cell death, probably through several mechanisms, including attenuated calpain activation during reperfusion leading to preserved cytoskeletal integrity and accelerated recovery of Na+/K+-ATPase function, but probably also protein kinase G (PKG)-mediated improved calcium handling. The potential role of gap junctions in preconditioning protection is controversial, but the recently discovered mitochondrial localisation of connexin43 seems to play an important role in protection that has not yet been completely defined. Several recent studies suggest that IP can reduce MPTP opening during reperfusion and limit infarct size through this mechanism, although the contribution of this widely accepted mechanism to the infarct size reduction induced by IP in the intact heart needs to be established.
Cardiovasc Res 2006 May 01
PMID:The end-effectors of preconditioning protection against myocardial cell death secondary to ischemia-reperfusion. 1663 42

Sarcolemmal sodium (Na) and calcium (Ca) currents are fundamentally involved in shaping the cardiac action potential. Alterations in Na or Ca currents can change action potential characteristics and therefore might result in cardiac arrhythmias. Also, these ions contribute to excitation-contraction coupling and therefore are important in myocyte shortening and contractility of the heart. This review article summarizes how sarcolemmal Na and Ca channels are regulated with an emphasis on the novel role of Ca-dependent proteins Calmodulin (CaM) and especially Ca/CaM-dependent protein kinase II (CaMKII) to modulate sarcolemmal Na and Ca channels in the heart.
J Cardiovasc Electrophysiol 2006 May
PMID:Modulation of cardiac Na(+) and Ca(2+) currents by CaM and CaMKII. 1668 79

Pulmonary hypertension is a devastating disorder, characterized by vascular proliferation, intimal hypertrophy and vasoconstriction. In this disorder, alterations in the nitric oxide pathway have borne out to be important in not only vascular proliferation, but also in the maintenance of vascular tone. After synthesis by soluble guanylate cyclase, cGMP effects vasodilation via protein kinase G and other mediators, and is hydrolyzed by phosphodiesterases (PDEs). PDE5 is abundantly expressed in the mammalian lung and its inhibition by sildenafil has been demonstrated to improve pulmonary vascular physiology in vitro and in vivo animal models of pulmonary hypertension. Recent human data has confirmed the efficacy of sildenafil in therapy for humans with pulmonary arterial hypertension. The following review will discuss the underlying basic science supporting the use of sildenafil, as well as human evidence supporting the critical role of this drug in therapy of patients with pulmonary hypertension.
Expert Rev Cardiovasc Ther 2006 May
PMID:Sildenafil, a PDE5 inhibitor, in the treatment of pulmonary hypertension. 1671 91

Transient outward channels have a different impact on action potential configuration in small mammals compared to large mammals. Small mammals depend primarily on Ito1 for repolarization, while in larger animals Ito1 only indirectly determines action potential duration by setting the level of the plateau. Transient outward channel expression and distribution also differ between animal species. Nevertheless, the primary protein sequence of the underlying Kv1.4, Kv4.2 and Kv4.3 alpha1-subunits displays remarkably high levels of amino acid identity. Transient outward channels are subject to alpha- and beta-adrenergic regulation, mainly decreasing Ito1. However, adrenergic stimulation is also an important determinant of transient outward channel downregulation in cardiac disease. Adrenergic stimulation of PKA as well as PKC leads to an inhibition of Ito1, which has been correlated with phosphorylation of the Kv1.4, Kv4.2 and Kv4.3 alpha1-subunits. Calmodulin-dependent kinase II, on the other hand, has been shown to be involved in an increase of Ito1. Comparison of Kv1.4, Kv4.2 and Kv4.3 primary amino acid sequences demonstrates a strong conservation of (potential) phosphorylation sites between different species, despite the fact that Ito1 has a different effect on action potential configuration in mammalian species.
Cardiovasc Res 2006 Aug 01
PMID:Molecular aspects of adrenergic modulation of the transient outward current. 1676 31

In several cellular systems, amino acids synergize with insulin in promoting protein synthesis through the activation of the protein kinases p70/S6-K and PHAS-1. Such activations are mediated by the upstream kinase: mammalian target of rapamycin (mTor). In this work we have investigated the intracellular pathways involved in insulin-induced and amino acid-induced p70/S6-K activations in human endothelial cells. In human umbilical vein endothelial cells, insulin induces the phosphorylation of p70/S6-K at 5 minutes decreasing thereafter, whereas amino acids alone or associated with insulin phosphorylate p70/S6-K at all the time points analyzed (60 minutes). Insulin and amino acids phosphorylate p70/S6-K by mTor-dependent and phosphotidylinositol 3-kinase-dependent mechanisms, whereas the mitogen-activated protein kinase pathway is involved only when p70/S6-K is activated by insulin. Insulin induces the phosphorylation of Akt and extracellular signal-regulated protein kinase (ERK) 1/2, whereas amino acids did not. Moreover, amino acids suppress the phosphorylations induced by insulin. The inhibitory effects of amino acids are reverted by the mTor inhibitor rapamycin. Insulin-induced phosphorylation of Akt (at 15 and 30 minutes) is not accompanied by the phosphorylation of the downstream kinase p70/S6-K, indicating the existence of a negative feedback at this level. Our data demonstrate that at the level of human endothelial cells, amino acids synergize with insulin in the phosphorylation of the kinase that lies downstream mTor, as p70/S6-K, whereas they inhibit the upstream kinases Akt and extracellular signal-regulated protein kinase 1/2 when activated by insulin, by an mTor-dependent mechanism.
J Cardiovasc Pharmacol 2006 May
PMID:In human endothelial cells amino acids inhibit insulin-induced Akt and ERK1/2 phosphorylation by an mTOR-dependent mechanism. 1677 2


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